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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Human Organic Anion Transporter 3 Gene Is Regulated Constitutively and Inducibly via a cAMP-Response Element

Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Kyoto University, Kyoto, Japan

Received for publication May 22, 2006
Accepted June 28, 2006.

	Abstract

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Human organic anion transporter (OAT) 3 (SLC22A8) is localized to the basolateral membranes of renal tubular epithelial cells and plays a critical role in the excretion of anionic compounds. We previously reported that interindividual variation in the OAT3 mRNA level corresponded to interindividual differences in the rate of renal excretion of cefazolin. However, there is little information available on the molecular mechanisms regulating the gene expression of OAT3. Therefore, in the present study, we examined the transcriptional regulation of human OAT3. A deletion analysis of the OAT3 promoter suggested that the region spanning -214 to -77 base pairs was essential for basal transcriptional activity. This region contained a perfectly conserved cAMP-response element (CRE), and a mutation here led to a reduction in promoter activity. Electrophoretic mobility shift assays showed that CRE-binding protein (CREB)-1 and activating transcription factor (ATF)-1 bound to CRE. The activity of the OAT3 promoter was increased through the phosphorylation of CREB-1 and ATF-1 by treatment with 8-bromo-cAMP. This paper reports the first characterization of the human OAT3 promoter and shows that CREB-1 and ATF-1 function as constitutive and inducible transcriptional regulators of the human OAT3 gene via CRE.

We previously found that the mRNA level of OAT3 was higher than that of any other member of the organic ion transporter (SLC22A) family in the human kidney, and OAT3 was localized to the basolateral membranes of proximal tubules (Motohashi et al., 2002). OAT3 possessed greater activity to transport cephalosporin antibiotics, including cefazolin than OAT1 in vitro experiment (Ueo et al., 2005). Furthermore, clinical pharmacokinetic and gene expression analyses showed that only the mRNA level of OAT3 among OAT1-4 significantly correlated with the apparent elimination rate constant of the free fraction of cefazolin in patients with mesangial proliferative glomerulonephritis (r = 0.757; p < 0.01) (Sakurai et al., 2004, 2005).

The OAT3 mRNA level is assumed to be mainly under the control of transcriptional regulation. However, little is known about the functional characteristics of the promoter region of OAT3. Based on this background, we cloned the human OAT3 promoter region and examined its promoter activity using opossum kidney (OK) cells. This is the first report to identify the cis-element and trans-factors for the regulation of the human OAT family in the kidney.

	Materials and Methods

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Materials. [-³²P]ATP was obtained from GE Healthcare (Little Chalfont, Buckinghamshire, UK). Restriction enzymes were from New England Biolabs (Beverly, MA). Antibodies used for supershift assays were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Those used for Western blotting were purchased from Cell Signaling Technology Inc. (Beverly, MA). 8-Bromo-cAMP sodium salt (8-Br-cAMP) was obtained from Sigma-Aldrich (St. Louis, MO).

5'-Rapid Amplification of cDNA Ends. To identify the transcription start site of human OAT3, 5'-rapid amplification of cDNA ends (RACE) was carried out using Human Kidney Marathon-Ready cDNA (Clontech, Mountain View, CA) according to the manufacturer's instructions. The primers for 5'-RACE were as follows: a gene-specific primer for OAT3 (accession no. NM_004254 [GenBank] ), 5'-CCCACTCTGTCACAATGGAGTCCTTGG-3' (473 to 446); and a nested gene-specific primer for OAT3, 5'-CCCATGCTTCCCACACGGTCCAGGATC-3' (177 to 151). The PCR products were subcloned into the pGEM-T Easy Vector (Promega, Madison, WI) and sequenced using a multicapillary DNA sequencer RISA384 system (Shimadzu, Kyoto, Japan).

Cloning of the 5'-Regulatory Region of the OAT3 Gene. Based on the human genomic sequence (accession no. NT_033903 [GenBank] ), the 2488-base pair flanking region upstream of the transcription start site was cloned by PCR using the primers listed in Table 1 and human genomic DNA (Promega). The PCR product was isolated by electrophoresis and subcloned into the firefly luciferase reporter vector pGL3-Basic (Promega), at NheI and XhoI sites. This full-length reporter plasmid is hereafter referred to as -2488/+21.

Preparation of Deletion Reporter Constructs. The -1862/+21 construct was generated by digestion of the -2488/+21 construct with SacI, and the 5'-deleted constructs (-926/+21, -214/+21) were generated by digestion of the -2488/+21 construct with MluI and either SpeI or ApaI. The ends were blunted with T4 DNA polymerase (Takara Bio, Otsu, Japan) and then self-ligated. The -77/+21 and -11/+21 constructs were generated by PCR with primers containing an NheI site and XhoI site (Table 1). The site-directed mutations in the putative CCAAT box and CRE were introduced into the -214/+21 construct with a QuikChange II site-directed mutagenesis kit (Stratagene, La Jolla, CA) with the primers listed in Table 1. The nucleotide sequences of these deleted or mutated constructs were verified.

Cell Culture, Transfection, and Luciferase Assay. OK cells were cultured in medium 199 (Invitrogen, Carlsbad, CA) containing 10% fetal bovine serum (Invitrogen) without antibiotics, in an atmosphere of 5% CO₂, 95% air at 37°C and subcultured every 7 days using 0.02% EDTA and 0.05% trypsin. OK cells were plated into 24-well plates (4 x 10⁶ cells/well) and transfected the following day with the reporter constructs and 25 ng of the Renilla reniformis vector pRL-TK (Promega), using Lipofectamine 2000 (Invitrogen) according to the manufacturer's recommendation. The firefly and Renilla activities were determined 48 h after the transfection using a dual-luciferase assay kit (Promega) and a LB940 luminometer (Berthold, Bad Wildbad, Germany). The firefly activity was normalized to Renilla activity. For the protein kinase A (PKA) stimulation experiment, the cells were treated with 1 mM 8-Br-cAMP for 12 h before the luciferase assay.

Electrophoretic Mobility Shift Assay. Nuclear extract was prepared from OK cells according to the method of Shimakura et al. (2005). The double-stranded oligonucleotides used in the EMSA are listed in Table 1. The OAT3 probe (-101/-75) was end-labeled with [-³²P]ATP using T4 polynucleotide kinase (Takara Bio), and the labeled probe was purified through a Sephadex G-25 column (GE Healthcare). EMSA was performed according to Alimov et al. (2003) but with some modifications. The OK nuclear extract (10 µg) was incubated in binding buffer [120 mM KCl, 20 mM Tris-HCl, pH 7.5, 1.5 mM EDTA, 2 mM dithiothreitol, 5% glycerol, 0.5% 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate, 10 mM NaF, 100 µM Na₃VO₄, and 2% protease inhibitor cocktail] for 30 min at 4°C. Thereafter, the labeled probe was added, and the mixture was incubated for a further 30 min at 4°C. For competition experiments and supershift assays, excess (50-fold) unlabeled oligonucleotide and antibodies (1 µg) were added 30 min before the addition of the labeled probe, respectively. The volume of the binding mixture was 20 µl throughout the experiment. The DNA-protein complex was then separated on a 4% polyacrylamide gel for 1.5 h at 200 V and room temperature in 0.5x Tris borate-EDTA buffer. Gels were dried and exposed to X-ray film for autoradiography.

Western Blot Analysis. OK cells were treated with phosphate-buffered saline in the presence or absence of 1 mM 8-Br-cAMP for 15 min before the preparation of nuclear extracts. Twenty micrograms of nuclear extract was separated on a 10% SDS polyacrylamide gel and transferred onto a polyvinylidene difluoride membrane (Immobilon-P; Millipore Corporation, Billerica, MA). Membrane blocking and antibody incubations were carried out using the PhosphoPlus CREB (Ser133) Antibody kit (Cell Signaling Technology Inc.) according to the manufacturer's instructions. The bound antibody was detected on X-ray film by enhanced chemiluminescence with horse-radish peroxidase-conjugated anti-rabbit IgG antibody (GE Healthcare).

Data Analysis. The results were expressed relative to pGL3-Basic and represent the mean ± S.D. of three replicates. Two or three experiments were conducted, and representative results are shown. In the mutational and PKA stimulation experiments, the statistical analysis was performed with the one-way analysis of variance followed by Scheffé F-post hoc testing.

	Results

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Determination of the Transcription Start Site of OAT3. Sequencing of the longest RACE product showed that the terminal position of OAT3 cDNA was located 126 nucleotides above the start codon, which was 10 base pairs downstream of the 5' end of OAT3 cDNA registered in the National Center for Biotechnology Information database (accession no. NM_004254 [GenBank] ). Therefore, the 5' end of OAT3 cDNA was numbered with +1 as the transcription start site in this study.

Determination of Minimal OAT3 Promoter. To determine the minimal region required for basal activity of the promoter, a series of deletion constructs were transfected into OK cells, and luciferase activity was measured (Fig. 1A). OK cells were used in the luciferase assay because they have an organic anion transport system (Hori et al., 1993), and the transcription factors and/or cofactors required for the expression exist intrinsically in these cells. The longest reporter constructs (-2488/+21) showed an approximately 14-fold increase in luciferase activity compared with pGL3-Basic in OK cells, but they had little promoter activity in human embryonic kidney 293 cells, which lack an organic anion transport system (Fig. 1B). The 5'-deleted constructs (-1862/+21, -926/+21, -214/+21) had the same level of activity as the longest construct, -2488/+21. In contrast, the -77/+21 construct had one-sixth of the activity of -214/+21. These results suggested that the elements important for the basal promoter activity were located between -214 and -77.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Identification of the transcriptional activity of the human OAT3 promoter in OK cells. A, deletion analysis of the human OAT3 promoter in OK cells. A series of deleted promoter constructs [equimolar amounts of the -2488/+21 construct (500 ng)] were transfected into OK cells for luciferase assays. B, transcriptional activity of the human OAT3 promoter in human embryonic kidney 293 cells. Firefly luciferase activity was normalized to Renilla luciferase activity. Data are reported as the relative -fold increase compared with pGL3-Basic and represent the mean ± S.D. of three replicates.

View larger version (19K): [in this window] [in a new window]   Fig. 2. Nucleotides sequence of the promoter region (-220 to -1) of human OAT3. Numbering is relative to the transcription start site. The putative binding sites for the transcription factors are indicated (the arrows indicate the direction).

Mutagenesis of CCAAT Box and CRE. To determine whether these sites were important for the promoter activity of OAT3, mutations at these sites (designated as mCCAAT and mCRE, respectively) were introduced in the -214/+21 construct and transfected into OK cells. As shown in Fig. 3, mCCAAT and mCRE reduced the luciferase activity to two-third and one-third of the wild-type level, respectively. These results suggest that the CCAAT box and CRE are responsible for the basal promoter activity of OAT3.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Mutational analysis of the putative CCAAT box and CRE of the human OAT3 promoter. A, schematic of the mutated OAT3 (-214/+21) reporter constructs. B, these constructs (500 ng) were transfected into OK cells for luciferase assays. Firefly luciferase activity was normalized to Renilla luciferase activity. Data are reported as the relative -fold increase compared with pGL3-Basic and represent the mean ± S.D. of three replicates. *, significantly different from wild type; p < 0.05.

View larger version (63K): [in this window] [in a new window]   Fig. 4. EMSA using nuclear extract from OK cells and a human OAT3 probe (-101/-75). A, nuclear extract from OK cells was incubated with the 32P-labeled OAT3 oligonucleotide probe (-101/-75) alone (lane 2) or in the presence of excess unlabeled oligonucleotide (-101/-75) (lane 3), excess mutated oligonucleotide (lane 4-6), and excess Sp1 oligonucleotide (lane 7). In lane 1, nuclear extract was not added. B, nuclear extract from OK cells was incubated with the 32P-labeled OAT3 oligonucleotide probe (-101/-75) alone (lane 2) or in the presence of antibody against ATF-1 (lane 3), ATF-2 (C-19) (lane 4), ATF-2 (N-96) (lane 5), ATF-3 (lane 6), CREB-1 (lane 7), CREB-2 (lane 8), c-Jun (lane 9), and CCAAT/enhancer-binding protein (lane 10). In lane 1, nuclear extract was not added. Arrows indicate the supershifted complexes.

It has been demonstrated that various transcription factors bind to CRE (Hai and Hartman, 2001). Figure 4B shows results of supershift assays using antibodies against transcription factors that bind to CRE. Antibodies against activating transcription factor (ATF)-1 and CRE-binding protein (CREB)-1 were able to supershift the DNA-protein complex (Fig. 4B, lanes 3 and 7). In contrast, antibodies against ATF-2, ATF-3, CREB-2 (ATF-4), c-Jun, and CCAAT/enhancer-binding protein did not result in a supershift (Fig. 4B, lanes 4-6 and 8-10). These results indicate that the transcription factor, which binds to CRE, consists entirely of a homodimer or heterodimer made up of ATF-1 and/or CREB-1.

Effect of PKA Activation. Both ATF-1 and CREB-1 are phosphorylated by PKA and activate the transcription of target genes. The effect of the PKA activator 8-Br-cAMP on the activity of the OAT3 promoter was investigated with the -214/+21, mCRE, and -77/+21 constructs in OK cells. Treatment with 8-Br-cAMP increased luciferase activity 2.5-fold in the -214/+21 construct. In contrast, the response to 8-Br-cAMP was diminished in the mCRE and -77/+21 constructs (Fig. 5). As shown in Fig. 6, levels of phosphorylated CREB-1 and ATF-1 increased with 8-Br-cAMP treatment. These results suggested that PKA stimulated the OAT3 promoter through phosphorylation of both CREB-1 and ATF-1.

View larger version (13K): [in this window] [in a new window]   Fig. 5. Effect of 8-Br-cAMP on the promoter activity of various reporter constructs. These constructs (500 ng) were transfected into OK cells for luciferase assays. 8-Br-cAMP (1 mM) was added to the medium 36 h after transfection, and luciferase assays were carried out after 12 h. Firefly luciferase activity was normalized to Renilla luciferase activity. Open columns and closed columns indicate control and 8-Br-cAMP treatment, respectively. Data are reported as the relative -fold increase compared with pGL3-Basic and represent the mean ± S.D. of three replicates. *, significantly different from control; p < 0.05.

View larger version (21K): [in this window] [in a new window]   Fig. 6. Western blot analyses of nuclear extracts from OK cells treated without (lanes 1-3) or with 1 mM 8-Br-cAMP for 15 min (lanes 4-6), and total cell extracts from SK-N-MC cells, prepared without or with forskolin/3-isobutyl-1-methylxanthine (IBMX) treatment, to serve as negative and positive controls. Nuclear extracts or total cell extract (20 µg) was separated on a 10% SDS polyacrylamide gel and blotted onto a polyvinylidene difluoride membrane. Phospho-CREB (Ser133) antibody (A) and CREB antibody (B) (1:1000 dilution) were used as primary antibodies. Horseradish peroxidase-conjugated anti-rabbit IgG antibody was used for detection of bound antibodies. The arrowheads indicate the positions of each transcription factor.

	Discussion

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Soodvilai et al. (2004) demonstrated that the transport activity of rabbit OAT3 is up-regulated by PKA (10-min stimulation) and speculated that this effect is due to the transfer of additional OAT3 transporters from an intracellular compartment to the basolateral cell membrane. Conversely, we showed that phosphorylation of CREB-1 and ATF-1 by PKA through the stimulation of 8-Br-cAMP (12 h) increased the promoter activity of OAT3. The present study revealed another possible molecular mechanism for the activation of PKA to stimulate the transport activity of OAT3, although it is unclear whether the rabbit OAT3 promoter has a CRE. It is therefore suggested that the short-term as well as long-term regulation of OAT3 is mediated by the activation of PKA. Further studies are needed to clarify the physiological and pharmacological implications of PKA signaling for the transport activity of OAT3.

In this study, a mutation in the CCAAT box reduced the luciferase activity, although no proteins bound to the CCAAT box in the EMSA experiments. Such a mutation may affect the function of CREB-1 and reduce the luciferase activity because the CCAAT box is in the vicinity of the CRE. It was reported that mutations that disrupted sequences located 5' and 3' of the CRE (TTACGTCA) in the promoter of the phosphoenolpyruvate carboxylkinase gene caused less severe reductions in basal promoter activity (Quinn et al., 1988), suggesting that not only the CRE but also the regions around the CRE are important for the constitutive transcriptional regulation of OAT3.

To clarify the interindividual variation in the pharmacokinetics of drugs, single-nucleotide polymorphisms (SNPs) in the coding region (cSNP) of drug transporters have been investigated (Ishikawa et al., 2004). Erdman et al. (2006) examined the allele frequency of several cSNPs in the OAT3 gene and transport characteristics and found that allele frequencies of cSNPs, which resulted in a completed loss of function, were very low (Xu et al., 2005; Erdman et al., 2006). In addition, the cSNP of OAT3 was considered to be unlikely to influence the pharmacokinetics of drugs (Nishizato et al., 2003; Sakurai et al., 2005). Recent studies have demonstrated that SNP in the promoter region (regulatory SNP; rSNP) is a candidate for the cause of the variation in the pharmacokinetics among individuals. Analyses of rSNP in the multidrug resistance 1 gene suggested that several SNPs comprise a haplotype, influencing multidrug resistance 1 mRNA expression (Taniguchi et al., 2003; Takane et al., 2004). Screening of the rSNP of OAT3 is needed to identify the genomic information affecting the mRNA level of OAT3. Alternatively, the regulation or modulation of CREB-1 may be involved in the interindividual difference in OAT3 mRNA levels.

View larger version (16K): [in this window] [in a new window]   Fig. 7. Schematic model of transcriptional regulation of the human OAT3 gene. CREB-1 and ATF-1 bind to CRE and activate the transcription of the OAT3 gene (constitutive expression). PKA further activates the transcription of the OAT3 gene through phosphorylation of both CREB-1 and ATF-1 (inducible expression).

	Footnotes

 
This work was supported in part by the 21st Century Center of Excellence (COE) program "Knowledge Information Infrastructure for Genome Science"; a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a grant-in-aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan. J.A. is supported as a research assistant by the 21st Century COE program "Knowledge Information Infrastructure for Genome Science".

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.106.108233.

ABBREVIATIONS: OAT, organic anion transporter; OK, opossum kidney; 8-Br-cAMP, 8-bromo-cAMP; RACE, rapid amplification of cDNA ends; PCR, polymerase chain reaction; PKA, protein kinase A; EMSA, electrophoretic mobility shift assay; CRE, cAMP-response element; mut, mutation/mutated; ATF, activating transcription factor; CREB, CRE-binding protein; SNP, single-nucleotide polymorphism; cSNP, coding single-nucleotide polymorphism; rSNP, regulatory single-nucleotide polymorphism.

Address correspondence to: Prof. Ken-ichi Inui, Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui{at}kuhp.kyoto-u.ac.jp

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